The natural systemic autoimmune disease syndromes of inbred and crossbred New Zealand mice are widely accepted laboratory animal models of human diseases of unknown etiology: systemic lupus erythematosus, autoimmune hemolytic anemia, and lymphoma/leukemia. We have shown that the natural history of the murine disease is related to the expression of an endogenous murine type C RNA tumor virus and to pathogenetic antibody responses both to self antigens, including thymocytes, and to endogenous viral protein antigens, mainly the subviral envelope glycoprotein. An objective of this project is further to elucidate and integrate the genetic, viral, and immunological (including thymic) determinants of autoimmune and leukemic diseases in the animal model and to apply the knowledge gained to the study of cause and control of corresponding human diseases. We have microscopically located a type C viral protein-related antigen in the tissue lesions and immune deposits in human systemic lupus erythematosus. The further characterization of the nature and significance of this antigen in human disease and the proposed study of host cell regulation of integrated type C viral genes in the animal model may lead to better understanding of the mechanisms of development of naturally occurring autoimmune and leukemic diseases and other forms of cancer.